Recent advances in the therapeutic applications of selenium nanoparticles.

Selenium nanoparticles (SeNPs) are an appealing carrier for the targeted delivery. The selenium nanoparticles are gaining global attention because of the potential therapeutic applications in several diseases e.g., rheumatoid arthritis (RA), inflammatory bowel disease (IBD), asthma, liver, and various autoimmune disorders like psoriasis, cancer, diabetes, and a variety of infectious diseases. Despite the fact still there is no recent literature that summarises the therapeutic applications of SeNPs. There are some challenges that need to be addressed like finding targets for SeNPs in various diseases, and the various functionalization techniques utilized to increase SeNP's stability while facilitating wide drug-loaded SeNP distribution to tumor areas and preventing off-target impacts need to focus on understanding more about the therapeutic aspects for better understanding the science behind it. Keeping that in mind we have focused on this gap and try to summarize all recent key targeted therapies for SeNPs in cancer treatment and the numerous functionalization strategies. We have also focused on recent advancements in SeNP functionalization methodologies and mechanisms for biomedical applications, particularly in anticancer, anti-inflammatory, and anti-infection therapeutics. Based on our observation we found that SeNPs could potentially be useful in suppressing viral epidemics, like the ongoing COVID-19 pandemic, in complement to their antibacterial and antiparasitic uses. SeNPs are significant nanoplatforms with numerous desirable properties for clinical translation.

The evidence for repurposing anti-epileptic drugs to target cancer.

Antiepileptic drugs are versatile drugs with the potential to be used in functional drug formulations with drug repurposing approaches. In the present review, we investigated the anticancer properties of antiepileptic drugs and interlinked cancer and epileptic pathways. Our focus was primarily on those drugs that have entered clinical trials with positive results and those that provided good results in preclinical studies. Many contributing factors make cancer therapy fail, like drug resistance, tumor heterogeneity, and cost; exploring all alternatives for efficient treatment is important. It is crucial to find new drug targets to find out new antitumor molecules from the already clinically validated and approved drugs utilizing drug repurposing methods. The advancements in genomics, proteomics, and other computational approaches speed up drug repurposing. This review summarizes the potential of antiepileptic drugs in different cancers and tumor progression in the brain. Valproic acid, oxcarbazepine, lacosamide, lamotrigine, and levetiracetam are the drugs that showed potential beneficial outcomes against different cancers. Antiepileptic drugs might be a good option for adjuvant cancer therapy, but there is a need to investigate further their efficacy in cancer therapy clinical trials.

Understanding translational research in schizophrenia: A novel insight into animal models.

Schizophrenia affects millions of people worldwide and is a major challenge for the scientific community. Like most psychotic diseases, it is also considered a complicated mental disorder caused by an imbalance in neurotransmitters. Due to the complexity of neuropathology, it is always a complicated disorder. The lack of proper understanding of the pathophysiology makes the disorder unmanageable in clinical settings. However, due to recent advances in animal models, we hope we can have better therapeutic approaches with more success in clinical settings. Dopamine, glutamate, GABA, and serotonin are the neurotransmitters involved in the pathophysiology of schizophrenia. Various animal models have been put forward based on these neurotransmitters, including pharmacological, neurodevelopmental, and genetic models. Polymorphism of genes such as dysbindin, DICS1, and NRG1 has also been reported in schizophrenia. Hypothesis based on dopamine, glutamate, and serotonin are considered successful models of schizophrenia on which drug therapies have been designed to date. New targets like the orexin system, muscarinic and nicotinic receptors, and cannabinoid receptors have been approached to alleviate the negative and cognitive symptoms. The non-pharmacological models like the post-weaning social isolation model (maternal deprivation), the isolation rearing model etc. have been also developed to mimic the symptoms of schizophrenia and to create and test new approaches of drug therapy which is a breakthrough at present in psychiatric disorders. Different behavioral tests have been evaluated in these specific models. This review will highlight the currently available animal models and behavioral tests in psychic disorders concerning schizophrenia.

Targeting Breast Cancer Signaling via Phytomedicine and Nanomedicine.

BACKGROUND: The development of breast cancer (BC) and how it responds to treatment have both been linked to the involvement of inflammation. Chronic inflammation is critical in carcinogenesis, leading to elevated DNA damage, impaired DNA repair machinery, cell growth, apoptosis, angiogenesis, and invasion. Studies have found several targets that selectively modulate inflammation in cancer, limit BC's growth, and boost treatment effectiveness. Drug resistance and the absence of efficient therapeutics for metastatic and triple-negative BC contribute to the poor outlook of BC patients. SUMMARY: To treat BC, small-molecule inhibitors, phytomedicines, and nanoparticles are conjugated to attenuate BC signaling pathways. Due to their numerous target mechanisms and strong safety records, phytomedicines and nanomedicines have received much attention in studies examining their prospects as anti-BC agents by such unfulfilled demands. KEY MESSAGES: The processes involved in the affiliation across the progression of tumors and the spread of inflammation are highlighted in this review. Furthermore, we included many drugs now undergoing clinical trials that target cancer-mediated inflammatory pathways, cutting-edge nanotechnology-derived delivery systems, and a variety of phytomedicines that presently address BC.

Discovery of oxindole-based FLT3 inhibitors as a promising therapeutic lead for acute myeloid leukemia carrying the oncogenic ITD mutation.

FMS-like tyrosine kinase 3 (FLT3) mutations occur in approximately 30% of acute myeloid leukemia (AML) patients. In the current study, the oxindole chemotype is employed as a structural motif for the design of new FLT3 inhibitors as potential hits for AML irradiation. Cell-based screening was performed with 18 oxindole derivatives and 5a-c inhibited 68%-73% and 83%-91% of internal tandem duplication (ITD)-mutated MV4-11 cell growth for 48- and 72-h treatments while only 0%-2% and 27%-39% in wild-type THP-1 cells. The most potent compound 5a inhibited MV4-11 cells with IC50 of 4.3 µM at 72 h while it was 8.7 µM in THP-1 cells, thus showing two-fold selective inhibition against the oncogenic ITD mutation. The ability of 5a to modulate cell death was examined. High-throughput protein profiling revealed low levels of the growth factors IGFBP-2 and -4 with the blockage of various apoptotic inhibitors such as Survivin. p21 with cellular stress mechanisms was characterized by increased expression of HSP proteins along with TNF-ß. Mechanistically, compounds 5a and 5b inhibited FLT3 kinase with IC50 values of 2.49 and 1.45 µM, respectively. Theoretical docking studies supported the compounds' ability to bind to the FLT3 ATP binding site with the formation of highly stable complexes as evidenced by molecular dynamics simulations. The designed compounds also provide suitable drug candidates with no violation of drug likeability rules.

Combination of an Oxindole Derivative with (-)-ß-Elemene Alters Cell Death Pathways in FLT3/ITD+ Acute Myeloid Leukemia Cells.

Acute myeloid leukemia (AML) is one of the cancers that grow most aggressively. The challenges in AML management are huge, despite many treatment options. Mutations in FLT3 tyrosine kinase receptors make the currently available therapies less responsive. Therefore, there is a need to find new lead molecules that can specifically target mutated FLT3 to block growth factor signaling and inhibit AML cell proliferation. Our previous studies on FLT3-mutated AML cells demonstrated that ß-elemene and compound 5a showed strong inhibition of proliferation by blocking the mutated FLT3 receptor and altering the key apoptotic genes responsible for apoptosis. Furthermore, we hypothesized that both ß-elemene and compound 5a could be therapeutically effective. Therefore, combining these drugs against mutated FLT3 cells could be promising. In this context, dose-matrix combination-based cellular inhibition analyses, cell morphology studies and profiling of 43 different apoptotic protein targets via combinatorial treatment were performed. Our studies provide strong evidence for the hypothesis that ß-elemene and compound 5a combination considerably increased the therapeutic potential of both compounds by enhancing the activation of several key targets implicated in AML cell death.

Can Natural Products Targeting EMT Serve as the Future Anticancer Therapeutics?

Cancer is the leading cause of death and has remained a big challenge for the scientific community. Because of the growing concerns, new therapeutic regimens are highly demanded to decrease the global burden. Despite advancements in chemotherapy, drug resistance is still a major hurdle to successful treatment. The primary challenge should be identifying and developing appropriate therapeutics for cancer patients to improve their survival. Multiple pathways are dysregulated in cancers, including disturbance in cellular metabolism, cell cycle, apoptosis, or epigenetic alterations. Over the last two decades, natural products have been a major research interest due to their therapeutic potential in various ailments. Natural compounds seem to be an alternative option for cancer management. Natural substances derived from plants and marine sources have been shown to have anti-cancer activity in preclinical settings. They might be proved as a sword to kill cancerous cells. The present review attempted to consolidate the available information on natural compounds derived from plants and marine sources and their anti-cancer potential underlying EMT mechanisms.

Flavonoids as promising molecules in the cancer therapy: An insight.

Cancer continues to increase global morbidity and mortality rates. Despite substantial progress in the development of various chemically synthesized anti-cancer drugs, the poor prognosis of the disease still remains a big challenge. The most common drawback of conventional cancer therapies is the emergence of drug resistance eventually leading to the discontinuation of chemotherapy. Moreover, advanced target-specific therapies including immunotherapy and stem cell therapy are expensive enough and are unaffordable for most patients in poorer nations. Therefore, alternative and cheaper therapeutic strategies are needed to complement the current cancer treatment approaches. Phytochemicals are bioactive compounds produced naturally by plants and have great potential in human health and disease. These compounds possess antiproliferative, anti-oxidant, and immunomodulatory properties. Among the phytochemicals, flavonoids are very effective in treating a wide range of diseases from cardiovascular diseases and immunological disorders to cancer. They scavenge reactive oxygen species (ROS), inhibit cancer metastasis, modulate the immune system and induce apoptotic or autophagic cell death in cancers. This review will discuss the potential of various phytochemicals particularly flavonoids in attempts to target various cancers.

Immunosuppressive effects of morphine on macrophage polarization and function.

Macrophages play a pivotal role in safeguarding against a broad spectrum of infections, from viral, bacterial, fungal to parasitic threats and contributing to the immune defense against cancer. While morphine's immunosuppressive effects on immune cells are extensively documented, a significant knowledge gap exists regarding its influence on macrophage polarization and differentiation. Hence, we conducted a study that unveils that prior exposure to morphine significantly impedes the differentiation of bone marrow cells into macrophages. Furthermore, the polarization of macrophages toward the M1 phenotype under M1-inducing conditions experiences substantial impairment, as evidenced by the diminished expression of CD80, CD86, CD40, iNOS, and MHCII. This correlates with reduced expression of M1 phenotypical markers such as iNOS, IL-1ß, and IL-6, accompanied by noticeable morphological, size, and phagocytic alterations. Further, we also observed that morphine affected M2 macrophages. These findings emphasize the necessity for a more comprehensive understanding of the impact of morphine on compromising macrophage function and its potential ramifications for therapeutic approaches.

A novel strategy to elicit enduring anti-morphine immunity and relief from addiction by targeting Acr1 protein nano vaccine through TLR-2 to dendritic cells.

Morphine addiction poses a significant challenge to global healthcare. Current opioid substitution therapies, such as buprenorphine, naloxone and methadone are effective but often lead to dependence. Thus, exploring alternative treatments for opioid addiction is crucial. We have developed a novel vaccine that presents morphine and Pam3Cys (a TLR-2 agonist) on the surface of Acr1 nanoparticles. This vaccine has self-adjuvant properties and targets TLR-2 receptors on antigen-presenting cells, particularly dendritic cells. Our vaccination strategy promotes the proliferation and differentiation of morphine-specific B-cells and Acr1-reactive CD4 T-cells. Additionally, the vaccine elicited the production of high-affinity anti-morphine antibodies, effectively eliminating morphine from the bloodstream and brain in mice. It also reduced the expression of addiction-associated µ-opioid receptor and dopamine genes. The significant increase in memory CD4 T-cells and B-cells indicates the vaccine's ability to induce long-lasting immunity against morphine. This vaccine holds promise as a prophylactic measure against morphine addiction.

Future perspectives of emerging novel drug targets and immunotherapies to control drug addiction.

Substance Use Disorder (SUD) is one of the major mental illnesses that is terrifically intensifying worldwide. It is becoming overwhelming due to limited options for treatment. The complexity of addiction disorders is the main impediment to understanding the pathophysiology of the illness. Hence, unveiling the complexity of the brain through basic research, identification of novel signaling pathways, the discovery of new drug targets, and advancement in cutting-edge technologies will help control this disorder. Additionally, there is a great hope of controlling the SUDs through immunotherapeutic measures like therapeutic antibodies and vaccines. Vaccines have played a cardinal role in eliminating many diseases like polio, measles, and smallpox. Further, vaccines have controlled many diseases like cholera, dengue, diphtheria, Haemophilus influenza type b (Hib), human papillomavirus, influenza, Japanese encephalitis, etc. Recently, COVID-19 was controlled in many countries by vaccination. Currently, continuous effort is done to develop vaccines against nicotine, cocaine, morphine, methamphetamine, and heroin. Antibody therapy against SUDs is another important area where serious attention is required. Antibodies have contributed substantially against many serious diseases like diphtheria, rabies, Crohn's disease, asthma, rheumatoid arthritis, and bladder cancer. Antibody therapy is gaining immense momentum due to its success rate in cancer treatment. Furthermore, enormous advancement has been made in antibody therapy due to the generation of high-efficiency humanized antibodies with a long half-life. The advantage of antibody therapy is its instant outcome. This article's main highlight is discussing the drug targets of SUDs and their associated mechanisms. Importantly, we have also discussed the scope of prophylactic measures to eliminate drug dependence.

Revolutionizing medicine with toll-like receptors: A path to strengthening cellular immunity.

Toll-like receptors play a vital role in cell-mediated immunity, which is crucial for the immune system's defense against pathogens and maintenance of homeostasis. The interaction between toll-like-receptor response and cell-mediated immunity is complex and essential for effectively eliminating pathogens and maintaining immune surveillance. In addition to pathogen recognition, toll-like receptors serve as adjuvants in vaccines, as molecular sensors, and recognize specific patterns associated with pathogens and danger signals. Incorporating toll-like receptor ligands into vaccines can enhance the immune response to antigens, making them potent adjuvants. Furthermore, they bridge the innate and adaptive immune systems and improve antigen-presenting cells' capacity to process and present antigens to T cells. The intricate signaling pathways and cross-talk between toll-like-receptor and T cell receptor (TCR) signaling emphasize their pivotal role in orchestrating effective immune responses against pathogens, thus facilitating the development of innovative vaccine strategies. This article provides an overview of the current understanding of toll-like receptor response and explores their potential clinical applications. By unraveling the complex mechanisms of toll-like-receptor signaling, we can gain novel insights into immune responses and potentially develop innovative therapeutic approaches. Ongoing investigations into the toll-like-receptor response hold promise in the future in enhancing our ability to combat infections, design effective vaccines, and improve clinical outcomes.

Nano-drug delivery system: a promising approach against breast cancer.

Breast cancer (BC) is among the most frequent malignancies women face around the globe. Nanotherapeutics are constantly evolving to overcome the limitations of conventional diagnostic and therapeutic approaches. Nanotechnology-based nanocarriers have a higher entrapment efficiency, low cytotoxicity, greater stability and improved half-life than conventional therapy. Nano-drug delivery systems have improved pharmacokinetics and pharmacodynamics parameters because of nanomeric size. Currently, various nano-formulations are in preclinical and clinical settings for breast cancer, like polymeric nanoparticles, micelles, nanobodies, magnetic nanoparticles, liposomes, niosomes, gold-nanoparticles, dendrimers and carbon-nanotubes. This review highlights the recent advancement in developing nano-drug delivery systems for BC treatment. This review will open the gateway to researchers to understand the current approaches to developing nano-formulation and improving problems associated with conventional therapy.

The impact of aging-induced gut microbiome dysbiosis on dendritic cells and lung diseases.

Aging is an inevitable natural process that impacts every individual, and understanding its effect on the gut microbiome and dendritic cell (DC) functionality in elderly subjects is crucial. DCs are vital antigen-presenting cells (APCs) that orchestrate the immune response, maintaining immune tolerance to self-antigens and bridging innate and adaptive immunity. With aging, there is a shift toward nonspecific innate immunity, resulting in a decline in adaptive immune responses. This alteration raises significant concerns about managing the health of an elderly population. However, the precise impact of aging and microbiome changes on DC function and their implications in lung-associated diseases remain relatively understudied. To illuminate this subject, we will discuss recent advancements in understanding the connections between aging, gut dysbiosis, DCs, and lung diseases. Emphasizing the key concepts linking age-related gut microbiome changes and DC functions, we will focus on their relevance to overall health and immune response in elderly individuals. This article aims to improve our understanding of the intricate relationship between aging, gut microbiome, and DCs, potentially benefiting the management of age-associated diseases and promoting healthy aging.

Influence of chronic administration of morphine and its withdrawal on the behaviour of zebrafish.

Morphine is a potent analgesic opiate used to treat chronic pain, mostly in cancer patients. In addition, it is widely used as a drug of abuse. Due to the continuous rise of morphine-associated addiction, there is an urgent need to develop pre-clinical animal models to understand the behavioural pattern of drug dependence and its withdrawal. Recently, the experimental use of zebrafish has attained significance in behavioural neuroscience studies. The literature on zebrafish is conflicting with regard to morphine withdrawal symptoms. Unfortunately, no single model provides comprehensive details to evaluate zebrafish behaviour on opiate exposure. Further, the current models have various limitations, such as short duration, complexity of phenotypes, intricate quantification, and difficulty in studying withdrawal symptoms. Consequently, a firm standardization of the protocol to understand the influence of opiates on physiological and psychological behaviours is required. In this study, we have tried to overcome the shortcomings associated with the existing models and to optimize the protocols involving an array of parameters. We observed that the administration of morphine caused a significant increase in zebrafish behavioural patterns of spiral movements, circular movements, erratic movements, upper transitions, water surface transitions, wall licking, wall licking with upper transitions, wall licking with lower transitions, absolute angle changes, and time spent in the upper compartment. A decline in the freezing bouts and time spent in the lower compartment were noticed. In essence, this study offers a zebrafish model to comprehensively examine changes in behaviour of animals on opiate dependence and its withdrawal. The present study also reported that in zebrafish, the influence of chronic exposure of morphine modulates key gene targets involved in behaviour, neuroinflammation, and autophagy, which directly or indirectly are associated with morphine addiction in a chronic morphine model.

Drug Repurposing: A New Hope in Drug Discovery for Prostate Cancer.

Prostate cancer (PCA), the most common cancer in men, accounted for 1.3 million new incidences in 2018. An increase in incidences is an issue of concern that should be addressed. Of all the reported prostate cancers, 85% were detected in stages III and IV, making them difficult to treat. Conventional drugs gradually lose their efficacy due to the developed resistance against them, thus requiring newer therapeutic agents to be used as monotherapy or combination. Recent research regarding treatment options has attained remarkable speed and development. Therefore, in this context, drug repurposing comes into the picture, which is defined as the "investigation of the off-patent, approved and marketed drugs for a novel therapeutic indication" which saves at least 30% of the time and cost, reducing the cost of treatment for patients, which usually runs high in cancer patients. The anticancer property of cardiac glycosides in cancers was tested in the early 1980s. The trend then shifts toward treating prostate cancer by repurposing other cardiovascular drugs. The current review mainly emphasizes the advantageous antiprostate cancer profile of conventional CVS drugs like cardiac glycosides, RAAS inhibitors, statins, heparin, and beta-blockers with underlying mechanisms.

Comparative phytochemical composition, oleuropein quantification, antioxidant and cytotoxic properties of Olea europaea L. leaves.

In the present research, oleuropein (OLE) contents from two Saudi Arabian wild olive trees (Olea europaea L.) leaves (O1 and O2), were collected from two nearby geographical sites differing in altitudes, and were determined via UHPLC-MS analysis. Moreover, total bioactive contents, antioxidant, and cytotoxicity (against MCF-7 and MDA-MB-231 cells) potential were also evaluated. The sample (O2) was found to contain significantly (p < 0.05) higher OLE content (4.13 ± 1.0 mg/g DW) compared with the sample (O1) having OLE content (3.63 ± 1.1 mg/g DW). A similar trend was observed regarding total bioactive contents and antioxidant potential. However, both samples exhibited low cytotoxicity against tested cell lines. Furthermore, with hierarchical cluster analysis that compared the results of our samples (O1 and O2) to other samples reported in the literature, it was found that the variance in OLE content and biological activities from Al Baha region leaves had a resemblance to other reported superior cultivars.

Infection Prevalence at a Tertiary Hospital in Hail, Saudi Arabia: A Single-Center Study to Identify Strategies to Improve Antibiotic Usage.

Objective: Identifying the burden of disease and the condition of the Saudi population is in high demand from both a surveillance and analytical standpoint. The objective of this study was to determine the most prevalent infections among hospitalized patients (both community-acquired and hospital-acquired), the antibiotics prescribing pattern, and their relationship with patient characteristics like age and gender. Methods: A retrospective study was conducted comprising 2646 patients with infectious diseases or complications admitted to a tertiary hospital in the Hail region of Saudi Arabia. A standardized form was used to collect information from patient's medical records. Demographic data such as age, gender, prescribed antibiotics, and culture-sensitivity tests were included in the study. Results: Males represented about two-thirds (66.5%, n = 1760) of the patients. Most patients (45.9%) who suffered from infectious diseases were between the ages of 20 and 39. The most prevalent infectious ailment was respiratory tract infection (17.65%, n = 467). Furthermore, the most common multiple infectious diseases were gallbladder calculi with cholecystitis (40.3%, n = 69). Similarly, COVID-19 had the greatest impact on people over 60. Beta-lactam antibiotics were the most commonly prescribed (37.6%), followed by fluoroquinolones (26.26%) and macrolides (13.45%). But performing culture sensitivity tests were rather uncommon (3.8%, n = 101). For multiple infections, beta-lactam antibiotics (such as amoxicillin and cefuroxime) were the most commonly prescribed antibiotics (2.26%, n = 60), followed by macrolides (such as azithromycin and Clindamycin) and fluoroquinolones (eg, ciprofloxacin and levofloxacin). Conclusion: Respiratory tract infections are the most prevalent infectious disease among hospital patients, who are primarily in their 20s. The frequency of performing culture tests is low. Therefore, it is important to promote culture sensitivity testing in order to support the prudent use of antibiotics. Guidelines for anti-microbial stewardship programs are also highly recommended.

Physician's Knowledge and Attitudes on Antibiotic Prescribing and Resistance: A Cross-Sectional Study from Hail Region of Saudi Arabia.

BACKGROUND: Antibiotic (AB) resistance is caused partly by overuse, varies by region, and is influenced by prescriber perspectives. This study sought to determine physicians' knowledge and attitudes toward AB prescribing, particularly in the Hail region of Saudi Arabia. METHODS: An interdisciplinary team created and validated an electronic questionnaire via the test-retest method that measured reliability and consistency. The 19 questions covered the following subjects: demographic information (7), experience with AB resistance in daily work (3), AB prescribing behavior (2), communication with patients regarding AB resistance (3), and prescribing practices (4). The revised questionnaire was prepared and distributed to physicians in the Hail region via multiple electronic communication channels. Inferences were drawn based on descriptive statistics and multivariate regression analysis. RESULTS: The questionnaire responses of 202 participants were eligible for analysis. A total of 70 (34.80%) participants were general practitioners, 78 (38.12%) were engaged in daily work that was only mildly related to AB resistance, and 25 (12.37%) performed work that was substantially related to AB resistance. A total of 88 (43.56%) physicians believed that prescribing behavior contributed to the emergence of AB resistance, whereas 68 (33.66%) did not. Regarding exposure, 51 (25.24%) physicians reported encountering instances of AB resistance monthly, whereas 104 (51.48%) reported seeing cases of AB resistance very rarely. In terms of prescribing practices, 99 (49.0%) physicians prescribed ABs to patients daily and 73 (36.13%) weekly. Regarding AB-resistance-related communication with patients, 73 (36.13%) physicians frequently discussed AB resistance with patients suffering from infections, whereas 13 (6.4%) never discussed it with patients. CONCLUSION: General practitioners in the Hail region exhibited comprehensive awareness of the elements that contribute to AB resistance but only rarely communicated about the issue with their patients, presuming the latter to be oblivious to the science behind AB resistance. Our findings suggest that the features underlying practitioners' AB prescribing behavior could be a powerful strategy for lowering AB resistance.